Heart rate variability density analysis (Dyx) for identification of appropriate implantable cardioverter defibrillator recipients among elderly patients with acute myocardial infarction and left ventricular systolic dysfunction.

AIMS: Dyx is a new heart rate variability (HRV) density analysis specifically designed to identify patients at high risk for malignant ventricular arrhythmias. The aim of this study was to test if Dyx can improve risk stratification for malignant ventricular tachyarrhythmias and to test if the previously identified cut-off can be reproduced. METHODS AND RESULTS: This study included 248 patients from the CARISMA study with ejection fraction ≤40% after an acute myocardial infarction and an analysable 24 h Holter recording. All patients received an implantable cardiac monitor, which was used to diagnose the primary endpoint of near-fatal or fatal ventricular tachyarrhythmias likely preventable by an implantable cardioverter defibrillator (ICD), during a period of 2 years. A Dyx ≤ 1.96 was considered abnormal. The secondary endpoint was cardiovascular death. At enrolment 59 patients (24%) had a Dyx ≤ 1.96 and 20 experienced a primary endpoint. A Dyx ≤ 1.96 was associated with a significantly increased risk for malignant arrhythmias [hazards ratio (HR) = 4.36 (1.81-10.52), P = 0.001] and cardiovascular death [HR = 3.47 (1.38-8.74), P = 0.008]. Compared with important clinical risk parameters (age >70 years and QRS > 120 ms), Dyx ≤ 1.96 significantly added predictive value (P = 0.0066). CONCLUSIONS: Dyx was a better predictor of ventricular tachyarrhythmias than the traditional measures of HRV and heart rate turbulence, particularly in the elderly. Dyx might be a useful tool for better selection of ICD candidates in the elderly population, since a normal Dyx in this group was associated with a very low risk for malignant ventricular arrhythmias.ClinicalTrials.gov Identifier NCT00145119.

Long-term anti-HBs antibody persistence following infant vaccination against hepatitis B and evaluation of anamnestic response: a 20-year follow-up study in Thailand.

Hepatitis B vaccine has been available worldwide since the mid-1980s. This vaccine was evaluated in a clinical trial in Thailand, conducted on subjects born to hepatitis B surface antigen positive and hepatitis B e-antigen positive mothers and vaccinated according to a 4-dose schedule at 0, 1, 2 and 12 mo of age and a single dose of hepatitis B immunoglobulin concomitantly at birth. All enrolled subjects seroconverted and were followed for 20 y to assess the persistence of antibody to the hepatitis B surface antigen (anti-HBs) (NCT00240539). At year 20, 64% of subjects had anti-HBs antibody concentrations≥10 milli-international units per milli liter (mIU/ml) and 92% of subjects had detectable levels (≥3.3 mIU/ml) of anti-HBs antibodies. At year 20, subjects with anti-HBs antibody titer<100 mIU/ml were offered an additional dose of hepatitis B virus (HBV) vaccine to assess immune memory (NCT00657657). Anamnestic response to the challenge dose was observed in 96.6% of subjects with an 82-fold (13.2 to 1082.4 mIU/ml) increase in anti-HBs antibody geometric mean concentrations. This study confirms the long-term immunogenicity of the 4-dose regimen of the HBV vaccine eliciting long-term persistence of antibodies and immune memory against hepatitis B for up to at least 20 y after vaccination.

Influence of time between last myocardial infarction and prophylactic implantable defibrillator implant on device detections and therapies. "Routine Practice" data from the SEARCH MI registry.

BACKGROUND: A multicenter European Registry, SEARCH-MI, was instituted in the year 2002 in order to assess patients' outcomes and ICD interventions in patients with a previous MI and depressed LV function, treated with an ICD according to MADIT II results. In this analysis, we evaluate the influence of the time elapsed between last myocardial infarction (MI) and prophylactic cardioverter defibrillator (ICD) implant on device activations. METHODS: 643 patients with left ventricular dysfunction (mean LVEF 26 ± 5%) and NYHA class I-III were prospectively followed for 1.8 ± 1.2 years in a multicenter registry. The population was divided into 3 groups according to the time between last MI and ICD implant: [1] from 40 days to less than 1.5 years; [2] from 1.5 to less than 7 years and [3] at least 7 years. RESULTS: The cumulative incidence of ventricular tachyarrhymias and appropriate device therapy (ATP or shock) were higher in patients implanted longer time from last MI (Gray's Test p=0.002 and p=0.013 respectively). No significant differences were seen in all cause mortality (Gray's Test p=0.618) or sudden cardiac death across the MI stratification groups (Gray's Test p=0.663). CONCLUSIONS: Patients implanted with an ICD longer after the MI have a higher chance of presenting ventricular tachyarrhythmias and appropriate ICD therapy, while no differences were seen in overall mortality. These observations may be important for improving patient targeting in sudden death prevention.

Long-term anti-HBs antibody persistence and immune memory in children and adolescents who received routine childhood hepatitis B vaccination.

This paper presents data from two studies that evaluated 5-y and 10-y persistence of antibodies against hepatitis B (HBV) surface antigen (anti-HBs) and immune response to an HBV vaccine challenge in children and adolescents who had received three doses of a HBV vaccine in infancy as part of routine clinical practice [NCT00519649/NCT00984139]. Anti-HBs antibody concentrations ≥ 10 mIU/ml persisted in 83.3% (95% confidence interval [CI]: 78.5­87.5) and 78.3% (95% CI: 73.1­83.0) of subjects aged 7­8 y and 12­13 y, respectively 5­10 y after infant vaccination. One month postchallenge dose, 98.2% (95% CI: 95.9­99.4) and 93.7% (95% CI: 90.2­96.2) of subjects in the two age groups, respectively had anti-HBs antibody concentrations ≥ 100 mIU/ml. Overall, 99.6% (95% CI: 98­100) and 97.2% (95% CI: 94.5­98.8) of subjects aged 7­8 y and 12­13 y mounted an anamnestic response to the HBV challenge dose, which was well-tolerated. Healthy children aged 7­8 y and adolescents aged 12­13 y received three doses of a monovalent pediatric HBV vaccine (10 µg of HBsAg) before 18 mo of age. Serum samples collected before and one month post-HBV vaccine challenge dose were tested for anti-HBs antibody concentrations. Safety assessments were made for the HBV vaccine challenge dose. A three-dose childhood HBV immunization regimen induced persistence of antibodies against HBV infection for 10 y, up to adolescence. This vaccination regimen also conferred long-term immune memory against HBV as evidenced by the strong anamnestic response to the HBV vaccine challenge, despite waning anti-HBs antibody levels.

Booster vaccination of pre-school children with reduced-antigen-content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine co-administered with measles-mumps-rubella-varicella vaccine: a randomized, controlled trial in children primed according to a 2 + 1 schedule in infancy.

BACKGROUND: Pertussis occurs in older children, adolescents and adults due to waning immunity after primary vaccination. Booster vaccination for pre-school children has been recommended in Italy since 1999. In this study (NCT00871000), the immunogenicity, safety and reactogenicity of a booster dose of reduced-antigen content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV; GSK Biologicals Boostrix™-Polio; 3-component pertussis) vs. full-strength DTPa-IPV vaccine (sanofi-pasteur--MSD Tetravac™; 2-component pertussis) was evaluated in pre-school Italian children. METHODS: Healthy children aged 5-6 y primed in a routine vaccination setting with three doses of DTPa-based vaccines were enrolled and randomized (1:1) in this phase IIIb, booster study to receive a single dose of dTpa-IPV or DTPa-IPV; the MMRV vaccine was co-administered. Antibody concentrations/titers against diphtheria, tetanus, pertussis and poliovirus 1-3 were measured before and one month post-booster. Reactogenicity and safety was assessed. RESULTS: 305 subjects were enrolled of whom 303 (dTpa-IPV = 151; DTPa-IPV = 152) received booster vaccination. One month post-booster, all subjects were seroprotected/seropositive for anti-diphtheria, anti-tetanus, anti-PT, anti-FHA and anti-poliovirus 1-3; 99.3% of dTpa-IPV and 60.4% of DTPa-IPV subjects were seropositive for anti-PRN; 98-100% of subjects were seropositive against MMRV antigens post-booster. Pain at the injection site (dTpa-IPV: 63.6%; DTPa-IPV: 63.2%) and fatigue (dTpa-IPV: 26.5%; DTPa-IPV: 23.7%) were the most commonly reported solicited local and general symptoms, during the 4-d follow-up period. No SAEs or fatalities were reported. CONCLUSIONS: The reduced-antigen-content dTpa-IPV vaccine was non-inferior to full-strength DTPa-IPV vaccine with respect to immunogenicity. The vaccine was well-tolerated and can be confidently used as a booster dose in pre-school children.

Seventeen-year antibody persistence in adults primed with two doses of an inactivated hepatitis A vaccine.

BACKGROUND AND OBJECTIVES: Antibody persistence and immune memory against hepatitis A (HAV) in adults in a low endemicity country, 15 y after immunisation with two doses of HAV vaccine has been demonstrated. This communication provides additional information on antibody persistence up to Year 17 from two of the longest follow-up studies [NCT00289757/NCT00291876]. METHODS: In two double-blind primary studies, healthy adults aged 17-40 y and 21-40 y, respectively received two doses of the HAV vaccine following a 0,6 mo or 0,12 mo schedule. Anti-HAV antibody concentrations were measured using an enzyme-linked immunoassay (cut-off: 15 mIU/ml) at Year 16 and Year 17. Subjects who became seronegative (anti-HAV < 15 mIU/ml) since previous reporting were offered a challenge dose, with anti-HAV antibody concentration measurements at Day 14 and Day 30 thereafter. RESULTS: At Year 17, 100% and 96.7% of subjects remained seropositive for anti-HAV antibodies following the 0, 6 mo and 0, 12 mo regimens, respectively (GMCs: 278 mIU/ml and 369 mIU/ml). One subject who became seronegative at Year 16 received a HAV challenge dose within the next 12 mo and mounted an anamnestic response. The challenge dose was well-tolerated. CONCLUSIONS: Both HAV immunisation regimens (0,6 mo and 0,12 mo) induced persistence of vaccine-induced antibodies against HAV for at least 17 y after primary vaccination.

Anti-HBs antibody persistence following primary vaccination with an investigational AS02(v)-adjuvanted hepatitis B vaccine in patients with renal insufficiency.

BACKGROUND: Three doses of the investigational AS02(v)-adjuvanted hepatitis B virus (HBV) vaccine HB-AS02 have been shown to induce more rapid seroprotection and higher anti-HBs antibody concentrations in patients with renal insufficiency than four doses of FENDrix™ (HB-AS04), an adjuvanted HBV vaccine licensed in Europe for use in this population. This study evaluated persistence of immune response up to 36 months after primary vaccination. METHODS: In this open, international, Phase III follow-up study, 151 pre-dialysis, peritoneal dialysis and hemodialysis patients ≥15 years of age received HB-AS02 at 0, 1, 6 months and 149 received HB-AS04 at 0, 1, 2, 6 months. Of these, 99 and 80 returned at Month 36, 76 and 62 of whom were eligible for inclusion in the Long-Term According-To-Protocol (LT-ATP) cohort for descriptive analysis of antibody persistence (mean age: 65.6 years). RESULTS: At Month 36, 89.5% of subjects in the HB-AS02 group and 72.6% of those in the HB-AS04 group had anti-HBs antibody concentrations ≥10 mIU/ml. Anti-HBs antibody concentrations were ≥100 mIU/ml in 82.9% and 35.5% of subjects, respectively. Anti-HBs geometric mean antibody concentrations were higher in the HB-AS02 group over the 36 months of follow-up. An exploratory "time to boost" analysis confirmed that subjects who received HB-AS02 were 2.54 times more likely than those who received HB-AS04 to have anti-HBs antibody concentrations ≥10 mIU/ml at Month 36 (p=0.013 [95% CI: 1.22, 5.31]). CONCLUSION: HB-AS02 candidate vaccine induces high and persistent anti-HBs antibody levels in pre-dialysis, peritoneal dialysis and hemodialysis patients, potentially reducing the need for booster doses in this population.

Clinical significance of late high-degree atrioventricular block in patients with left ventricular dysfunction after an acute myocardial infarction--a Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) substudy.

BACKGROUND: High-degree atrioventricular block (HAVB) is a frequent complication in the acute stages of a myocardial infarction associated with an increased rate of mortality. However, the incidence and clinical significance of HAVB in late convalescent phases of an AMI is largely unknown. The aim of this study was to assess the incidence and prognostic value of late HAVB documented by continuous electrocardiogram (ECG) monitoring in post-AMI patients with reduced left ventricular function. METHODS: The study included 286 patients from the CARISMA study with AMI and left ventricular ejection fraction of 40% or less. An insertable loop recorder was implanted 5 to 21 days after AMI for incessant arrhythmia surveillance. Furthermore, ECG documentation was supplemented by a 24-hour Holter monitoring conducted at week 6 post-AMI. The clinical significance of HAVB occurring more than 21 days after AMI was examined with respect to development of major heart failure events and major ventricular tachyarrhythmic events. RESULTS: During a median follow-up of 1.9 years (interquartile range 0.9-2.0), late HAVB was documented in 30 patients. The risk of major heart failure events (hazard ratio [HR] 4.08 [1.38-12.09], P = .01) and major ventricular tachyarrhythmic events (HR = 5.41 [1.88-15.58], P = .002) were significantly increased in patients who developed late HAVB. CONCLUSION: High-degree atrioventricular block documented by continuous ECG monitoring occurring more than 3 weeks after AMI is a frequent complication in post-AMI patients with left ventricular dysfunction. Furthermore, HAVB is associated with ominous prognostic implications of both potentially lethal arrhythmias and heart failure.

Persistence of antibodies 3 years after booster vaccination of adults with combined acellular pertussis, diphtheria and tetanus toxoids vaccine.

The duration of protection after vaccination with reduced antigen content diphtheria, tetanus and acellular pertussis vaccines (Tdap) is not known. Long-term post-vaccination serological data will help to improve understanding of the duration of humoral immunity and guide vaccination policy for the timing of repeat dose administration. The persistence of antibodies to Tdap antigens was measured 3 years after vaccination of adults 19-64 years of age with one of 2 Tdap vaccines (Boostrix(®), GlaxoSmithKline Biologicals; Tdap-B: or Adacel(®), Sanofi Pasteur; Tdap-A). In both groups, geometric mean concentrations for antibodies to diphtheria, tetanus, and pertussis vaccine antigens were decreased at year 3 relative to levels observed 1 month and 1 year following vaccination, but remained higher than pre-vaccination levels. Seroprotection rates for diphtheria and tetanus remained high for both Tdap vaccines (for diphtheria, 96.9% and 97.8% for the Tdap-B and Tdap-A groups, respectively; for tetanus, 98.1% and 99.6%, respectively).

Immunogenicity of the reduced-antigen-content dTpa vaccine (Boostrix(®)) in adults 55 years of age and over: a sub-analysis of four trials.

BACKGROUND: Older adults, especially those over 65 years, are at risk of more severe morbidity from diphtheria, tetanus and pertussis and may transmit pertussis to unvaccinated or not yet fully vaccinated infants, but data on their response to reduced-antigen-content tetanus, diphtheria and acellular pertussis (dTpa) vaccines are lacking. METHODS: A sub-analysis pooled immunogenicity results in 293 adults aged 55+ years (mean age 64.4 years) from four randomised, controlled clinical trials of dTpa vaccine (Boostrix(®), GlaxoSmithKline Biologicals) with or without IPV co-administration, or dTpa-IPV (Boostrix(®) IPV). RESULTS: Seroprotective antibody levels were achieved by 82.8% for diphtheria and 94.5% for tetanus. For pertussis antigens, the booster response rate, defined as initially seronegative subjects [<5EU/mL] reaching ≥5EU/mL; or a ≥2-fold increase in antibody concentration if initially seropositive was 89.2% for pertussis toxoid, 95.8% for filamentous haemagglutinin and 94.5% for pertactin. Post-booster geometric mean concentrations (GMC) increased for all antigens. Post-booster anti-tetanus and anti-PRN GMCs tended to be higher in 55- to 64-year olds than in those aged 65+. CONCLUSION: Larger numbers of subjects over 75 years are needed to better define responses in advanced age, but these data suggest that a single booster dose of dTpa or dTpa-IPV induces good immunological responses in most, and that these vaccines could be readily integrated into existing programmes.

Risk factors of self-terminating and perpetuating ventricular tachyarrhythmias in post-infarction patients with moderately depressed left ventricular function, a CARISMA sub-analysis.

AIMS: The present study aimed to assess whether there are differences in risk indicators for perpetuating ventricular tachyarrhythmias (pVT) and self-terminating ventricular tachyarrhythmias (stVT). METHODS AND RESULTS: Patients with acute myocardial infarction (AMI) and baseline left ventricular ejection fraction ≤ 40% (n = 292) received an implantable electrocardiogram loop recorder from 5 to 21 days after AMI and were followed up for 24 months to document arrhythmic events in the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study. Several risk markers, such as the inducibility to sustained ventricular tachycardia during programmed electrical stimulation (PES), the signal-averaged ECG QRS duration (SAECG-QRS), heart rate variability (HRV) and turbulence (HRT), T-wave alternans, and non-sustained ventricular tachycardia on Holter were analysed at 6 weeks after the AMI. During the follow-up, 26 patients (9%) experienced an stVT (≥ 16 beats and < 30 s), and 21 patients (7%) a pVT. The occurrence of non-sustained ventricular tachycardia on Holter significantly predicted stVT [hazard ratio (HR) = 2.90, 1.26-6.67, 95% confidence interval (CI), P = 0.01], but not pVT during the follow-up. The inducibility during PES (HR = 5.02, 1.85-13.60, 95% CI, P = 0.001), SAECG-QRS ≥ 130 ms (HR = 8.73, 3.38-22.56, 95% CI, P < 0.001), the short-term scaling exponent HRV parameter ≤ 0.77 (HR = 5.65, 2.12-15.10, 95% CI, P = 0.001), and HRT slope ≤ 1.75 ms/NN (HR = 4.57, 1.80-11.59, 95% CI, P = 0.001) were significant predictors of pVT, even after adjustments with relevant clinical parameters (P from < 0.01 to < 0.001), but did not significantly predict the occurrence of stVT (P from 0.35 to 0.75). CONCLUSION: Self-terminating ventricular tachyarrhythmia and pVT have differences in electrophysiological substrate and arrhythmia modifiers in post-AMI patients with moderate left ventricular dysfunction.

Risk markers of late high-degree atrioventricular block in patients with left ventricular dysfunction after an acute myocardial infarction: a CARISMA substudy.

AIMS: High-degree atrioventricular block (HAVB) after acute myocardial infarction (AMI) is associated with increased risk of mortality. Risk markers and predictors of HAVB occurring after AMI are largely unknown. The aim of this study was to assess the predictive value of risk markers derived from a series of non-invasive and invasive tests for the development of HAVB documented by an implantable loop recorder (ILR) in late convalescent phases of an AMI. METHODS AND RESULTS: The study included 292 patients with AMI and subsequent left ventricular dysfunction without prior HAVB or implanted pacemaker. An ILR was implanted for continuous arrhythmia surveillance. Risk stratification testing was performed at inclusion and 6 weeks after AMI. The tests included echocardiography, electrocardiogram (ECG), 24 h Holter monitoring, and an invasive electrophysiological study. High-degree atrioventricular block was documented in 28 (10%) patients during a median follow-up of 2.0 (0.4-2.0) years. Heart rate variability (HRV) measures and non-sustained ventricular tachycardia occurring at the week 6 Holter monitoring were highly predictive of HAVB. Power law slope <-1.5 ms(2)/Hz was the most powerful HRV parameter (HR = 6.02 [2.08-17.41], P < 0.001). CONCLUSION: Late HAVB development in post-AMI patients with left ventricular dysfunction can be predicted by risk stratification tests. Measures of HRV reflecting autonomic dysfunction revealed the highest predictive capabilities.

The incidence and prognostic significance of new-onset atrial fibrillation in patients with acute myocardial infarction and left ventricular systolic dysfunction: a CARISMA substudy.

BACKGROUND: The incidence and risk associated with new-onset atrial fibrillation (AF) occurring after discharge in patients with acute myocardial infarction (MI) remains unknown. OBJECTIVE: This study sought to describe the incidence and clinical risk associated with postdischarge new-onset AF in post-MI patients with left ventricular systolic dysfunction. METHODS: The population included 271 post-MI patients with left ventricular ejection fraction ≤ 40% and no history of previous AF from the Cardiac Arrhythmias and Risk Stratification after Acute Myocardial Infarction (CARISMA) study. All patients were implanted with an implantable cardiac monitor and followed up every 3 months for 2 years. Major cardiovascular events were defined as reinfarction, stroke, hospitalization for heart failure, or death. RESULTS: The risk of new-onset AF is highest during the first 2 months after the acute MI (16% event rate) and decreases until month 12 post-MI, after which the risk for new-onset AF is stable. The risk of major cardiovascular events was increased in patients with AF events ≥ 30 seconds (hazard ratio [95% CI] = 2.73 [1.35 to 5.50], P = .005), but not in patients with AF events lasting <30 seconds (hazard ratio [95% CI] = 1.17 [0.35 to 3.92], P = .80). More than 90% of all recorded AF events were asymptomatic. CONCLUSION: Using an implantable cardiac monitor, the incidence of new-onset AF was found to be 4-fold higher than earlier reported. In the study population, in which treatment with beta-blockers was optimized, the vast majority of AF events were asymptomatic, emphasizing the importance of using continuous monitoring for studies concerning AF in heart failure patients. A duration of 30 seconds or more identified clinically important AF episodes documented by an implantable cardiac monitor.

Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study.

BACKGROUND: Knowledge about the incidence of cardiac arrhythmias after acute myocardial infarction has been limited by the lack of traditional ECG recording systems to document and confirm asymptomatic and symptomatic arrhythmias. The Cardiac Arrhythmias and Risk Stratification After Myocardial Infarction (CARISMA) trial was designed to study the incidence and prognostic significance of arrhythmias documented by an implantable cardiac monitor among patients with acute myocardial infarction and reduced left ventricular ejection fraction. METHODS AND RESULTS: A total of 1393 of 5869 patients (24%) screened in the acute phase (3 to 21 days) of an acute myocardial infarction had left ventricular ejection fraction ≤40%. After exclusions, 297 patients (21%) (mean±SD age, 64.0±11.0 years; left ventricular ejection fraction, 31±7%) received an implantable cardiac monitor within 11±5 days of the acute myocardial infarction and were followed up every 3 months for an average of 1.9±0.5 years. Predefined bradyarrhythmias and tachyarrhythmias were recorded in 137 patients (46%); 86% of these were asymptomatic. The implantable cardiac monitor documented a 28% incidence of new-onset atrial fibrillation with fast ventricular response (≥125 bpm), a 13% incidence of nonsustained ventricular tachycardia (≥16 beats), a 10% incidence of high-degree atrioventricular block (≤30 bpm lasting ≥8 seconds), a 7% incidence of sinus bradycardia (≤30 bpm lasting ≥8 seconds), a 5% incidence of sinus arrest (≥5 seconds), a 3% incidence of sustained ventricular tachycardia, and a 3% incidence of ventricular fibrillation. Cox regression analysis with time-dependent covariates revealed that high-degree atrioventricular block was the most powerful predictor of cardiac death (hazard ratio, 6.75; 95% confidence interval, 2.55 to 17.84; P<0.001). CONCLUSIONS: This is the first study to report on long-term cardiac arrhythmias recorded by an implantable loop recorder in patients with left ventricular ejection fraction ≤40% after myocardial infarction. Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients with depressed left ventricular ejection fraction after acute myocardial infarction. Intermittent high-degree atrioventricular block was associated with a very high risk of cardiac death. Clinical Trial Registration- URL: http://www.ClinicalTrials.gov, Unique identifier: NCT00145119.

Autonomic dysfunction and new-onset atrial fibrillation in patients with left ventricular systolic dysfunction after acute myocardial infarction: a CARISMA substudy.

BACKGROUND: Atrial fibrillation (AF) increases morbidity and mortality in patients with previous myocardial infarction and left ventricular systolic dysfunction. The purpose of this study was to identify patients with a high risk for new-onset AF in this population using invasive and noninvasive electrophysiological tests. METHODS: The study included 271 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with an acute myocardial infarction (AMI) and left ventricular ejection fraction ≤40% without previous AF at enrollment. Within 21 days after the AMI, an implantable loop recorder was inserted and used to diagnose AF over the 2-year study duration. The following tests were performed: heart rate variability (HRV) and turbulence (HRT) analyses from repeated 24-hour Holter recordings, 2-dimensional (2D)-echocardiograms, exercise test, and programmed electrophysiologic stimulation. RESULTS: A total of 101 patients (37%) developed AF during the study. Predictive measures included several indexes of HRV including reduced low-frequency (LF) power from spectral HRV analysis (adjusted HR = 1.6, P = 0.034), HRT slope ≤2.5 (HR = 1.6, P = 0.032) and Detrended Fluctuation Analysis (DFA1) from HRV analysis (HR = 1.8, P = 0.011); all are measures of cardiac autonomic nervous system dysfunction. Combined with age >60 years, low values for LF, HRT slope, and DFA1 provided a powerful risk score for prediction of new-onset AF (1-2 points: HR = 4.3, P = 0.001, 3-4 points: HR = 7.0, P < 0.001). CONCLUSION: Abnormal HRV and HRT parameters, which are associated with disturbances in the cardiac autonomic regulation, are associated with increased risk of new-onset AF independently of conventional clinical risk variables.

Diastolic dysfunction predicts new-onset atrial fibrillation and cardiovascular events in patients with acute myocardial infarction and depressed left ventricular systolic function: a CARISMA substudy.

AIMS: The aim of this study was to investigate the association between diastolic dysfunction and long-term occurrence of new-onset atrial fibrillation (AF) and cardiac events in patients with acute myocardial infarction (AMI) and left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: The study was performed as a substudy on the CARISMA study population. The CARISMA study enrolled 312 patients with an AMI and LV ejection fraction

Attenuated recovery of heart rate turbulence early after myocardial infarction identifies patients at high risk for fatal or near-fatal arrhythmic events.

BACKGROUND: Autonomic dysfunction tends to improve over time after acute myocardial infarction (MI), but the clinical significance of autonomic remodeling is not well known. OBJECTIVE: The purpose of this study was to test the hypothesis that the amount of recovery of autonomic function early after MI is associated with a risk for serious arrhythmias. METHODS: The prognostic significance of autonomic remodeling after MI was assessed in one post-MI cohort [Cardiac Arrhythmia and Risk Stratification after Myocardial Infarction (CARISMA)] and validated in a second cohort [Risk Estimation After Infarction, Noninvasive Evaluation (REFINE)]. Changes in heart rate variability (DeltaHRV) and heart rate turbulence (DeltaHRT) were measured from 24-hour ECG recordings performed early (5-21 days) and later (6 weeks) after MI in CARISMA (n = 312). DeltaHRV and DeltaHRT were similarly measured from early (2-4 weeks) and later (10-14 weeks) post-MI recordings in REFINE (n = 322). RESULTS: HRV and HRT increased over time in both cohorts. Attenuated recovery of autonomic function, defined as DeltaHRT slope <2.0 ms/RR, was associated with a 9.4-fold (95% confidence interval 1.2-71.6; P = .03) higher risk of ECG-documented sustained ventricular tachycardia or ventricular fibrillation in CARISMA and a 7.0-fold (95% confidence interval 1.6-29.6; P = .009) higher risk of fatal or near-fatal events in REFINE. Changes in HRV and HRT were not predictive of nonarrhythmic death in either cohort. CONCLUSION: Attenuated recovery of autonomic function early after MI consistently predicts a higher risk of fatal or near-fatal arrhythmic events. A lack of improvement in HRT early after MI appears to be a specific marker for serious arrhythmic events.

Heart rhythm at the time of death documented by an implantable loop recorder.

AIMS: The aims of this study were to describe arrhythmias documented with an implantable loop recorder (ILR) in post-acute myocardial infarction (AMI) patients with left ventricular dysfunction at the time of death and to establish the correlation to mode of death. METHODS AND RESULTS: Post-mortem ILR device interrogations were analysed from patients dying in the CARISMA study. Mode of death was classified by a modified CAST classification. Twenty-six patients died with an implanted ILR. Of these, 16 had an electrocardiogram recorded at the time of death. Ventricular tachycardia (VT)/ventricular fibrillation (VF) was terminal rhythm in eight patients and bradyarrhythmias were observed in another eight patients. Of the deaths with peri-mortem recordings, seven were classified as sudden cardiac death (SCD). In six of these, VF was documented at the time of death. Six monitored deaths were classified as non-SCD (NSCD) of which only two had recordings of VT/VF, whereas four had bradyarrhythmias. All peri-mortem recordings in non-cardiac death (NCD) were bradyarrhythmia. CONCLUSION: Long-term monitoring in a population of post-AMI patients with left ventricular ejection fraction < or =40% showed that VT/VF and bradyarrhythmia each accounted for half of the recorded events at the time of death. The ILR confirmed that ventricular tachyarrhythmias are associated primarily with SCD, whereas bradyarrhythmias and electromechanical dissociation seems dominant in NSCD and NCD. The study was registered at ClinicalTrials.gov: NCT00145119.

Prevalence and risk factors related to infections of cardiac resynchronization therapy devices.

AIMS: Device-related infections (DRI) are not well understood in patients implanted with a cardiac resynchronization therapy (CRT) device. The aims of this study were: (i) to evaluate the prevalence of CRT DRI; (ii) to establish the factors predictive of CRT DRI. METHODS AND RESULTS: Between January 2001 and May 2007, CRT implantation was performed in 303 patients (247 men, 82%). The mean follow-up was 31 +/- 19 months. Population characteristics were a mean age of 70 +/- 10 years old; 56 female; aetiology includes (202 dilated and 101 ischaemic cardiomyopathy); NYHA class 3.2 +/- 0.3; LVEF (26 +/- 6%), and a QRS width of 171 +/- 31 ms. Thirteen patients developed a DRI: endocarditis in four, pocket erosion in three, pocket abscess in five, and septicaemia in one. The prevalence of DRI was 4.3%. By univariate analysis, predictive factors of DRI were: procedure time (skin to skin: median of 85 vs. 57.5 min; P = 0.03), re-intervention (54 vs. 6.5%; P < 0.0001), haematoma (31 vs. 8.6% P = 0.01), lead dislodgement (23 vs. 6.2%; P = 0.03), dialysis (23.1 vs. 1.72%; P = 0.003), and procedure type [CRT-ICD (8.6%) vs. CRT PM (1.6%) or system up-grade (1.5%); P = 0.03]. Significant correlations were found between re-intervention and lead dislodgement (r = 0.8; P < 0.001), haematoma (r = 0.2; P < 0.001). Four independent predictive factors of DRI were identified as procedure time (P = 0.002); dialysis (P = 0.0001); re-intervention (P = 0.006), and procedure type (CRT-ICD vs. other procedures; P = 0.01). CONCLUSION: This study found that the prevalence of CRT DRI is close to 4.3% at 2.6 years (1.7% per year incidence). Four independent predictive factors of infections were identified including re-intervention, procedure time, dialysis, and primo CRT-ICD implantation. These parameters should be part of the risk-benefit evaluation in patients selected for CRT implantation.

Clinical and arrhythmic outcomes after implantation of a defibrillator for primary prevention of sudden death in patients with post-myocardial infarction cardiomyopathy: The Survey to Evaluate Arrhythmia Rate in High-risk MI patients (SEARCH-MI).

AIMS: To evaluate clinical and arrhythmic outcomes in post-infarction cardiomyopathy patients implanted with a defibrillator (ICD) for primary prevention of sudden death. METHODS AND RESULTS: The SEARCH-MI registry is a European multi-centre, prospective, observational study enrolling patients after myocardial infarction, chronic left ventricular dysfunction and an ICD implanted for primary prevention of sudden death. Data on 556 patients with at least one recorded follow-up are presented. Survey to Evaluate Arrhythmia Rate in High-risk MI (SEARCH-MI) patients were sicker than those enrolled in MADIT-II with higher New York Heart Association class and left bundle branch block. Total mortality was 10.4%. Close to one-third (30%) of patients experienced episodes of sustained ventricular arrhythmia. One-quarter (23%) received at least one appropriate therapy and 10% inappropriate therapy. Gender (25% males vs. 5% females, P = 0.0009) and history of non-sustained ventricular tachycardia (24% with vs. 18% without P = 0.037) were predictive of appropriate ventricular therapy. CONCLUSION: SEARCH-MI represents the current clinical management of post-MI patients with left ventricular dysfunction indicated to defibrillator implant for primary prevention. European routine clinical practice was influenced by landmark trials and guidelines which impacted on the implantation of cardiac resynchronization therapy in over 25% of such patients. Non-sustained ventricular tachycardia identifies subjects with a higher incidence of appropriate ICD therapy.